Cutaneous T-cell lymphoma (CTCL) is a rare malignancy of skin-trafficking CD4+ T-cells. Patients with advanced disease with extensive skin and blood involvement have a poor prognosis and exhibit marked defects in cell mediated immunity. Underlying these defects is an associated profound decline in the numbers of peripheral blood dendritic cells (DCs) along with marked deficiencies in the ability of these cells to produce cytokines, including interleukin-12 (I-12) and interferon alpha (IFN alpha), which are critical for antitumor immunity. Because host immune function appears to play an integral role in mediating disease-controlling responses in CTCL, the investigators have been investigating a number of mechanisms for activating DCs in patients, including the use of resiquimod which has been recognized as powerfully immune stimulatory by virtue of activation of DCs following binding to Toll like receptors (TLR) 7 and 8. Preliminary data of the investigators indicate that resiquimod exhibits the capacity to induce in vitro the production of high levels of the immune stimulatory cytokines interleukin-12 (IL-12) and interferon (IFN) alpha from the peripheral blood cells of advanced CTCL patients which is associated with marked activation of natural killer (NK) cells and cluster of differentiation (CD) 8+ T-cells and upregulation of CD80/CD86 on apoptotic cells (APCs). This grant proposes an initial single center phase 1, open label trial of resiquimod gel which is highly bioavailable through the skin. Patients with CTCL will be monitored for 1) clinical responses, 2) adverse effects, and a unique series of in vivo immunological assays including 3) in vivo immune stimulatory effects including DC, NK and CD8 T-cell activation, and cutaneous intralesional infiltration with CD8+ cytotoxic T-cells and NK cells as well as their ability to produce IFN gamma.